Dynamic basis of fidelity and speed in translation: Coordinated multistep mechanisms of elongation and termination

Abstract

As the universal machine that transfers genetic information from RNA to protein, the ribosome synthesizes proteins with remarkably high fidelity and speed. This is a result of the accurate and efficient decoding of mRNA codons via multistep mechanisms during elongation and termination stages of translation. These mechanisms control how the correct sense codon is recognized by a tRNA for peptide elongation, how the next codon is presented to the decoding center without change of frame during translocation, and how the stop codon is discriminated for timely release of the nascent peptide. These processes occur efficiently through coupling of chemical energy expenditure, ligand interactions, and conformational changes. Understanding this coupling in detail required integration of many techniques that were developed in the past two decades. This multidisciplinary approach has revealed the dynamic nature of translational control and uncovered how external cellular factors such as tRNA abundance and mRNA modifications affect the synthesis of the protein product. Insights from these studies will aid synthetic biology and therapeutic approaches to translation.

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Binding of eEF2-GTP stabilizes the hybrid state, and promotes rapid GTP hydrolysis. The accompanying conformational changes reset the ribosome, with the deacylated tRNA released from the E site, the peptidyl-tRNA in the P site, and the vacant A site awaiting the next aminoacyl tRNA (reviewed in Dever and Green, 2012; Prabhakar et al, 2017). …”

“…Although cells grapple with a fundamental tradeoff between translation elongation accuracy and speed, the error rate under normal circumstances is quite low, and is estimated to be around one amino acid misincorporated for every 10 3 -10 4 codons. Errors in ribosome translocation leading to frameshifts, which are potentially more devastating to cellular fitness, are believed to be even more infrequent (reviewed in Prabhakar et al, 2017; Zaher and Green, 2009). The elongation factors eEF1A and eEF2 play essential roles in the delivery of the cognate aminoacyl tRNA to the A site of the ribosome and in its translocation along the mRNA after peptide bond formation, respectively.…”

Targeting Translation Termination Machinery with Antisense Oligonucleotides for Diseases Caused by Nonsense Mutations

“…Translation has been shown to be a tightly regulated, highfidelity process [9,10]. Translation termination occurs when the ribosome reads a stop codon and recruits translation termination factors, instead of aminoacyl-transfer RNAs (tRNAs), to the A-site of the ribosome.…”

Stochastic Simulation to Visualize Gene Expression and Error Correction in Living Cells

“…Indeed, such dependence was later seen at the single-molecule level [30]. But it now appears that some of the forward rates also depend on the identity of the tRNA [31,32,33], an effect sometimes called "internal discrimination." In the limit that the ribosome uses only internal discrimination (activation barrier heights of correct and incorrect tRNA binding differ and the equilibrium constants are the same), minimum error is obtained at fast catalytic rates [34].…”